5AWD

Crystal structure of human TLR8 in complex with N1-4-aminomethylbenzyl (IMDQ)

Summary for 5AWD

• Entry DOI: 10.2210/pdb5awd/pdb
• Related: 5AWA 5AWB 5AWC
• Descriptor: Toll-like receptor 8, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: immune system, tlr8, adjuvant, vaccine adjuvants, linnate immunity, glycosylation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 96665.06

Authors

Tanji, H.,Ohto, U.,Shimizu, T. (deposition date: 2015-07-03, release date: 2015-09-23, Last modification date: 2024-10-30)

Primary citation

Beesu, M.,Caruso, G.,Salyer, A.C.,Khetani, K.K.,Sil, D.,Weerasinghe, M.,Tanji, H.,Ohto, U.,Shimizu, T.,David, S.A.
Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.
J.Med.Chem., 58:7833-7849, 2015

PubMed Abstract: Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼ 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.

PubMed: 26351878
DOI: 10.1021/acs.jmedchem.5b01087

Experimental method

X-RAY DIFFRACTION (2.05 Å)